Immunologic homeostasis in the gastrointestinal (GI) tract involves the attenuation of inflammation in a compartment with more than 100 trillion bacteria. Homeostasis involves a variety of traits expressed by the host and the enteric bacterial commensals. The loss of this balance results in clinically important chronic mucosal inflammatory disorders, but the specific factors responsible for maintaining GI homeostasis are only partly understood. One emerging protective population is the mucosal B-cell, based on models of oral tolerance, chronic respiratory disease, and colitis. In this project, I characterize the functional phenotype and developmental requirements for a newly appreciated population at the host-bacterial interface, the intestinal intraepithelial lymphocyte (IEL) B-cell. Through genetic requirements, I will clarify the precursor B-cells filling this compartment. Through enteric bacterial and host genetic manipulations, I will determine how the formation/survival of this population is controlled by lumenal bacterial sensing by the TLR and B cell antigen receptor systems. My preliminary results support the feasibility of my key aims, and for a novel role of IEL B-cells in mucosal immune physiology.